— Bonus Article —
Medical Treatment of Diabetes Mellitus

Glycemic Treatment

Insulin sensitizers

Biguanides (metformin)

Metformin is the only available biguanide. Metformin should be used as a first-line therapy in patients with type 2 DM whenever possible.¹³ Metformin suppresses hepatic glucose output and primarily affects fasting glycemia; however, reduced postprandial glucose concentrations also occur.

The most common side effects of metformin are diarrhea, nausea, and abdominal discomfort. Metformin has the potential to produce very rare but life-threatening lactic acidosis (< 1 in 100,000). The use of metformin is contraindicated in patients with a glomerular filtration rate less than 30 mL/min, with acidosis, hypoxia, or dehydration.⁸

Metformin usually does not lead to hypoglycemia when used as monotherapy. It can lead to weight loss (3%–5% of body weight), and it has been shown to decrease plasma triglyceride concentrations (10%–20%).^8,14,15

Thiazolidinediones

Thiazolidinediones (TZDs) primarily enhance the insulin sensitivity of muscle and fat tissue and mildly enhance insulin sensitivity of the liver. TZDs lower fasting and postprandial blood glucose levels.

Major side effects of TZDs include weight gain, with an increase in subcutaneous adiposity, and fluid retention. Fluid retention typically manifests as peripheral edema, but heart failure can occur on occasion. These agents should be avoided in patients with functional class III or IV heart failure. The PROactive trial of the TZD pioglitazone found that pioglitazone did not increase cardiovascular risk compared with placebo.¹⁶ TZDs have been associated with an increased risk of fractures, particularly in women. When used as monotherapy, TZDs do not cause hypoglycemia. Pioglitazone lowers triglyceride levels, increases high-density lipoprotein cholesterol, and increases the low-density lipoprotein cholesterol particle size.^8,16–18

Insulin secretagogues

Insulin secretagogues such as sulfonylureas and glinides stimulate secretion of insulin from the pancreas regardless of the ambient glucose concentration.

Sulfonylureas

Sulfonylureas lower fasting and postprandial glucose levels. The main side effects include weight gain (about 2 kg upon initiation) and hypoglycemia. The UK Prospective Diabetes Study (UKPDS) trial showed a decrease in microvascular complications with the use of sulfonylureas.¹⁹ Caution should be used in patients with liver or kidney dysfunction or patients who frequently skip meals. Newer, second-generation sulfonylureas (ie, glipizide and glimepiride) may have less risk of hypoglycemia because their action is somewhat glucose dependent.^8,17,19

Glinides

Glinides, which include repaglinide and nateglenide, have a rapid onset of action and a short duration of action, so they are a good option for patients with erratically timed meals. Glinides have a lower risk of hypoglycemia than sulfonylureas. Caution must be used with glinides in patients with liver dysfunction. Dosing is immediately before meals.^8,17

Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors such as acarbose, miglitol, and voglibose block the enzyme alpha-glucosidase in the cells of the brush border of the small intestine, which delays absorption of carbohydrates. Alpha-glucosidase inhibitors primarily affect postprandial hyperglycemia without causing hypoglycemia. Abdominal cramps, bloating, flatulence, and diarrhea are the most common side effects. Use of alpha-glucosidase inhibitors should be avoided in patients with severe hepatic or renal impairment. Dosing is prior to carbohydrate-containing meals.^8,20

Incretin-based therapies

Therapies that target the incretin hormones to increase insulin production include glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors.

GLP-1 agonists

Exenatide, liraglutide, albiglutide, and dulaglutide are synthetic analogs of the GLP-1 hormone. GLP-1 is produced in the small intestine; it stimulates insulin secretion and inhibits glucagon secretion in a glucose-dependent manner. It also delays gastric emptying and suppresses appetite through central pathways. GLP-1 agonists primarily decrease postprandial blood glucose levels; however, a moderate reduction in fasting blood glucose and some weight loss can also occur.

The major side effects are gastrointestinal complaints such as nausea, vomiting, and diarrhea. Hypoglycemia does not occur unless GLP-1 analogues are combined with a sulfonylurea or insulin. There is a slightly increased risk of acute pancreatitis in patients using GLP-1 agonist medications, and patients must be warned to discontinue use of these medications if abdominal pain occurs.

Dosing of GLP-1 agonist medications is either twice daily, daily, or weekly by subcutaneous injection.^8,21

DPP-4 inhibitors

DPP-4 is an enzyme that rapidly degrades GLP-1. Suppression of DPP-4 leads to higher levels of insulin secretion and suppression of glucagon secretion in a glucose-dependent manner.

The DPP-4 inhibitors such as linagliptin, sitagliptin, saxagliptin, and alogliptin are given orally once daily. An increased risk of acute pancreatitis has been reported in some patients. Dose reduction is needed in patients with renal impairment for most of these medications.^8,22

SLGT-2 inhibitors

SGLT-2 inhibitors include canagliflozin, dapagliflozin, and empagliflozin and are the newest group of antidiabetic medications. These medications inhibit glucose reabsorption in proximal tubule of the kidney leading to glycosuria, which lowers the blood glucose concentration, lowers blood pressure, and leads to some weight loss. Empagliflozin was shown to be cardioprotective in some patients.²³

SGLT-2 inhibitors are given once a day in the morning and the primary side effects are polyuria and genital yeast infections. These medications are contraindicated in patients with severe end-stage renal disease and those who are on dialysis.^8,24

Pramlintide (amylinomimetics)

Pramlintide, an amylinomimetic, is a synthetic drug that acts like amylin, a hormone secreted by beta cells that suppresses glucagon secretion, slows gastric emptying, and suppresses appetite through central pathways. Pramlintide acts primarily on postprandial blood glucose levels.

The side effects of pramlintide are gastrointestinal complaints, especially nausea. Currently, pramlintide is approved only as an adjunctive therapy with insulin, and it can be used in patients with type 1 DM or type 2 DM. The dose for type 1 DM is 15 µg before each meal subcutaneously, and for type 2 DM it is generally 60 µg before meals.²⁵

Dopamine-receptor agonist (bromocriptine)

Bromocriptine is a central dopamine-receptor agonist, and when given in rapid-release form within 2 hours of awakening in the morning, it improves glycemic control for patients with type 2 DM. The mechanism of action resulting in improved glycemic control is unknown. Studies have demonstrated the cardiovascular safety of bromocriptine.²⁶

Side effects of bromocriptine include hypotension, somnolence, and nausea. Individuals with psychiatric disorders may experience exacerbation while taking bromocriptine. Bromocriptine is taken with food to diminish nausea.²⁷

Insulin

Insulin and insulin analogues remain the most direct method of reducing hyperglycemia. There is no upper limit in dosing for therapeutic effect, so it can be used to bring any HbA1c down to near-normal levels. Other benefits of insulin include reducing triglyceride levels and increasing high-density lipoprotein cholesterol.

Hypoglycemia is a concern with use of insulin, and studies have shown that episodes for which the patient required assistance due to the hypoglycemia occurred between 1 and 3 times per 100 patient-years.¹³ Weight gain can occur after initiation of insulin therapy, and patients typically gain 2 kg to 4 kg.⁸